Cancer threatens human health and life. In recent years, researches on anticancer drugs have turned to the development of specific molecular targeted therapeutic drugs.
The p53 tumor suppresser protein plays a critical role in protection against development of tumor. In about 50% of human cancers the gene encoding the p53 protein occur mutation or deletion, resulting in loss of the transcriptional activity and the functions of the tumor suppressor protein. In the remaining 50% cases, direct interaction between p53 and human murine double minute 2 (MDM2) proteins plays a major role in inhibiting the functions of wild-type p53. Intervention of the interaction between MDM2-p53 with a small molecule has been considered as a new strategy for cancer treatment.
Since 2005, Wang Shaomeng et al. have reported a series of spiro-indolone analogs as inhibitors of MDM2-p53 interaction, and one (SAR405838/MI-77301) among this series of compounds has currently been in clinical development (see U.S. Pat. No. 7,759,383B2, U.S. Pat. No. 8,222,288B2, U.S. Pat. No. 8,680,132B2, US20130030173A1, WO2012065022A2, and WO2012155066A2). Swiss Roche Pharmaceuticals also reports a series of spiro-indolone analogs (see WO2011067185, WO2011134925, and WO2012022707) and a series of pyrrolidine analogs (see WO2013178570, WO2014206866, and WO2015000945), wherein RG7388 among the pyrrolidine analogs has been in clinical development. It has been shown that these compounds have limited solubility, greatly challenging the development of preparations which are stable in vivo and in clinical researches.
The existing compounds can only be used in oral preparations due to poor water solubility, and have compromised therapeutic effect against tumors in clinical due to severe gastrointestinal effects and low bioavailability. Accordingly, there is still a need for developing spiro-indolone analogs that have excellent solubility in water, low toxicity, and more potency and can be used in dosage forms for intravenous injection, as inhibitors of the MDM2-p53 interaction.